The present invention relates to a specialized device for whole-body hyperthermia, including extracorporeal blood heating and dialysis, as an antiviral protocol.
Whole body hyperthermia (WBHT) as a treatment for neoplasms has been carefully studied and applied since the 1960s (3,4,27). Prior to that period there were multiple reports of tumor regression coincident with induced fever. Biochemical studies of the effects of hyperthermia have indicated that temperatures greater than 41xc2x0 C. induce necrosis of some types of tumor (3,5). In the body, there are additional physiologic effects by which hyperthermia induces tumor necrosis. In both normal and tumorous tissue, hyperthermia causes an initial vasodilation of blood vessels with a resulting increase in blood flow. Then, there is a decrease in blood flow due to autoregulation and vasoconstriction (6). Tumor tissues have less vascular reactivity to autoregulate blood flow, and are therefore more prone than normal tissues to the effects of high temperature during either local hyperthermia or WBHT (7).
It is now generally accepted that hyperthermia is a useful therapy in treatment of cancers, and regional hyperthermia for accessible tumors is used in every major cancer therapy center in the U.S. Regional hyperthermia is a valuable adjunct to radiation and chemotherapy, because it carries low risk, has few side effects, and often exerts its best effects in patients whose lesions are unresponsive to radiation or chemotherapy (3). In metastatic solid tissue tumors, WBHT is used more than regional hyperthermia, since it is difficult to apply regional therapy to lesions in the abdomen or chest. Even in patients who have failed radiation or chemotherapy, there is a partial remission of the tumors in about half of the patients, and complete remission in a few patients. These results are similar to those obtained with many drugs; however, with drug therapy of cancer, the incidence of side-effects is approximately 100%. Though there are some side-effects of WBHT, most of them are short-lived and not serious.
Kaposi""s sarcoma (KS) is the most common neoplasm of patients with AIDS, being seen primarily in the male homosexual AIDS population (8). Unlike the classical KS, the AIDS-related form is often aggressive, presenting with multiple, large cutaneous tumors and early visceral dissemination. The etiology of KS in these patients is uncertain. Cytomegalic viral infections, other sexually transmitted organisms, volatile nitrate inhalation, oncogenes, hormones and HLA type have all been suggested as possible co-factors. KS is currently reported as the primary diagnosis in 13% of hospital admissions of all AIDS patients (9) and the disfiguring disease accounts for substantial morbidity.
Of all tumors, KS seems to be the most sensitive to systemic hyperthermia. In a 1985 survey of 21 patients treated with hyperthermia for cancer, the only patient with complete remission was one with KS (10). According to the investigators, this patient is the only one of the 21 treated who is still alive; the KS lesions have not recurred. A case report in 1990 indicated dramatic resolution of KS lesions during and shortly after a single WBHT treatment (11). These lesions had not recurred one year later (12) and have not recurred now, three years later. Since 1990, 31 patients with HIV and Kaposi""s sarcoma have been treated by WBHT, most of them in Rome, Italy. Most of the patients had remission of Kaposi""s lesions and diminished evidence of HIV for 4 months (120 days) after treatment (29).
Hyperthermia also helps to resolve many bacterial infections. The fever response in mammals evolved specifically for this reason, and beneficial effects of fever in survival of animals after gram negative blood infection has been reported (13). Hyperthermia also has a beneficial effect in resolution of many viral infections. Hornback and co-workers have studied infection of mice by Friend virus complex, a retrovirus complex similar to HIV which causes a uniformly fatal erythroleukemia in mice, with devastating effects on T-cells and natural killer cells similar to those of HIV. This disease can be partially controlled by WBHT at 40xc2x0 C. (once weekly for 2 weeks). Mice receiving WBHT after injection with Friend virus lived twice as long as untreated controls, and longer than those treated with cyclosporin alone (14,15). Natural killer cell function is also increased by the WBHT therapy versus controls (14,15).
The HIV virus is somewhat heat sensitive. McDougal, et al. incubated HIV at temperatures ranging from 37xc2x0 to 60xc2x0 and found the log kill followed first order kinetics (16). In the natural liquid state, HIV was 40% inactivated after 30 minutes at 42xc2x0 C., and 100% inactivated at 56xc2x0 C. (17). Importantly, HIV-infected lymphocytes are very effectively killed by 42xc2x0 C. temperature. Since only a small portion of lymphocytes are HIV infected, this means that the surviving cells will be free to perform their usual immunologic functions, unimpeded by HIV. Even if some HIV-infected lymphocytes do survive, they have a change in surface antigens to allow recognition by the immune system.
The beneficial effects of a single WBHT in treatment of HIV and Kaposi""s sarcoma are no longer a theoretical possibility but a demonstrated reality. One study indicates that of 31 patients with HIV and Kaposi""s sarcoma treated with WBHT, 70% had complete or partial regression of Kaposi""s sarcoma lesions and these patients had an increase of CD4 counts for an average of 120 days. Adenopathy and oral leukoplakia resolved in all patients. The treatment was most effective when the pre-treatment CD4 count was cover 50/mm3. In no patient was HIV activity stimulated by WBHT, as determined by many antigen markers (29).
An article by Milton B. Yatvin, PhD, indicates that xe2x80x9cthe initial effect of hyperthermia on cells is mediated via the heat-induced disorganization of membrane lipidsxe2x80x9d (28). This effect was further defined in later studies (18,19). Yatvin also described a variety of simple compounds which have fluidizing effects on lipid bilayer membranes similar to heat, and exert antiviral effects on HIV and other viral infections (including ethanol, anesthetics, AL721, adamantane, and a common food additive called butylated hydroxytoluene or BHT) (18). In later work, Yatvin suggested that the effects of heat on virally-loaded cells was enhanced by fluidizing chemical agents (27,18). These articles demonstrate that WBHT should have positive effects on HIV infection, and that these effects can be improved by addition of some simple chemicals during or before WBHT.
There are many methods for inducing WBHT including paraffin wax baths, radiant heat chambers, microwave heat chambers, water blankets, and extracorporeal blood heating. These methods have been used mostly in treatment of patients with far-advanced metastatic cancer. Even in these frail patients, core temperature can be maintained at 42xc2x0 C. for one to two hours without untoward effects on cardiovascular, renal, or liver function, though there usually is elevation of serum transaminases, creatinine phosphokinase, and lactate dehydrogenase (4). Three instances of mild neurologic damage were noted in Parks, patients in association with hypophosphatemia during treatment, but no significant problems occurred once phosphate levels were maintained (20). Larkin also reported two deaths in patients receiving WBHT at 41.5 to 42xc2x0 C. for 1xc2xd to 2 hours; however, these patients had massive tumors in the liver, and by-products of tumor necrosis contributed to the death of these patients (21). In review of prior studies Yatvin, Stowell and Steinhart found only 6 deaths in 275 hyperthermic treatments of debilitated patients with carcinoma, representing a mortality of only 2% (27).
Extracorporeal WBH is usually accomplished using a relatively simplistic circuit containing only a blood pump and a heat exchanger to heat the blood (22). The blood flow rate through the extracorporeal system has been high, at 2-3 liters per minute. During this procedure, and other WBH techniques, the patient is warmed to a core temperature of 41.5xc2x0 to 42xc2x0 C. for two hours or more. Sedation is required and often general anesthesia and intubation is performed (22). In the mildly sedated patient, the brain stem responds with hyperventilation, to increase heat loss. Blood alkalosis results, leading to decreases in potassium, calcium, phosphate, and magnesium (as these substances transfer into cells or bone) (23). In a generally anesthetized patient on mechanical ventilation, normal ventilation can be provided. However, the increased body metabolic rate and centralization of blood flow leads to acidosis, with increases in potassium, calcium, phosphate and magnesium (24). Frequent: blood chemistries must be measured during the treatment, so that these changes in blood chemistries can be corrected by intravenous infusion of various electrolytes. Following WBH, there is often a persisting deficiency in potassium, calcium, and phosphate unless these have been aggressively replaced during the treatment. Often, there is moderate damage to liver, muscles, and kidneys during the treatment, demonstrated by changes in enzyme and toxin levels in the blood (23,25,26).
Clinically recognizable complications of hyperthermia depend to some degree upon the method of administration, whether by direct skin contact, radiant heat, or heating of the blood, and on the core temperature obtained and length of exposure. Skin burns with hyperthermia generally occur only when created by skin contact or radiant heat. Studies in cancer patients have shown a significant incidence of fatigue, peripheral neuropathy, vomiting, diarrhea, and arrhythmias. However, these occurred mostly in severely debilitated patients with Karnofsky Scores less than 50% (1,2).
In treatment of patients with HIV and Kaposi""s sarcoma, hyperthermia also is relatively safe. In a study of 31 patients with HIV and Kaposi""s sarcoma treated by extracorporeal WBHT with a relatively low blood flow rate of 300-400 ml/min (29) there was no significant morbidity associated with the treatment, though two patients had intravascular coagulopathy (without signs of bleeding) and several patients had pressure point skin damage. There were two patient deaths within 120 days of the procedure, one from intracerebral bleed due to a pre-existing intracerebral Berry aneurysm (a rare condition) and one from pulmonary edema and cardiac arrhythmia following overly aggressive fluid therapy (in a patient who had pre-existing pulmonary disease). The overall mortality of this study was only 7%; the mortality rate would have been zero if patients with abnormal pulmonary status had been excluded from the study, and if the patient with the very rare cerebral vascular condition had not been treated.
Among the known protocols for extracorporeal heating of blood, various difficulties persist, including elevated serum transaminases and bilirubin, instances of neurologic damage associated with serum hypophosphatemia, risk due to abnormal pH or to abnormal sodium, sodium bicarbonate or potassium levels, and possible death from massive tumor necrosis. Previously attempted treatments of human immunodeficiency virus with hyperthermia have included only relatively minor measures to maintain normal blood physiology (the sodium bicarbonate addition of Davidner et al., for example). A need therefore remains for a more reliable, simpler and more comprehensive extracorporeal hyperthermia treatment, and an apparatus for performing such treatment, in which unwanted side effects are reduced or eliminated altogether. The present invention addresses this need.
One preferred embodiment of the invention provides an apparatus for use in whole body hyperthermia treatment of a patient. The inventive device comprises a dialyzer having a blood inlet to and a blood outlet from a blood side separated from a dialysate side by at least one dialysis membrane, said dialyzer further having a dialysate inlet to and dialysate outlet from said dialysate side. The apparatus further includes a blood circuit for conveying blood from the patient to said blood inlet and from said blood outlet back into the patient, and a pump operably associated with said blood circuit for circulating blood through said blood circuit. A heat exchanger is operably associated with the blood circuit and preferably effective to heat blood circulating in the blood circuit to a temperature of at least about 40xc2x0 C. A sorbent suspension is provided in the dialysate side of the dialyzer, which includes at least the components water, a particulate surface adsorptive agent, and precipitated calcium phosphate. Circulating means are also provided for circulating said sorbent suspension in said dialysate side of said dialyzer in a direction generally from said dialysate inlet to said dialysate outlet. A preferred device further includes a heater, such as an electrically-powered device which generates heat via resistance to electric current, associated with the dialysate side and effective to heat the sorbent suspensions to a temperature of at least about 40xc2x0 C.
Another preferred embodiment of the invention provides a composition for use as a dialysate in hemodialysis. The inventive composition comprises a sorbent suspension which includes water, a particulate surface adsorptive agent, a particulate cation exchanger, a surface active agent, and precipitated calcium phosphate.
Another preferred embodiment of the invention provides an apparatus for use in whole body hyperthermia in which relatively high rates of blood flow can be established in a hemodialysis instrument while maintaining proper sorbent mixing by the expansion and compression of compliant membranes of the instrument. The inventive apparatus comprises a dialyzer having a blood inlet to and a blood outlet from a blood side separated from a dialysate side by dialysis membranes, the dialyzer further having a dialysate inlet to and dialysate outlet from said dialysate side, the membranes being compliantly formed to expand and compress in response to alternating negative pressure and positive pressure on said dialysate side of the dialyzer so as to agitate a sorbent suspension to prevent settling. The apparatus also includes means for applying alternating negative pressure and positive pressure on the dialysate side of the dialyzer, and a blood circulation circuit. The blood circulation circuit includes a blood removal circuit for conveying blood from the patient to the blood inlet of the dialyzer, and a blood return circuit for conveying blood from the blood outlet back into the patient. The blood removal and return circuits are adapted for connection to the patient via separate accesses. One or more pumps operably associated with the blood circulation circuit are operable to circulate blood through the blood circulation circuit in a direction generally from the blood removal access to the blood return access. Bypass means fluidly connect the blood removal circuit to the blood return circuit, and allow blood circulated by the pump to bypass the dialyzer so as to reduce blood-side tensioning of the dialyzer membranes whereby effective mixing of the sorbent suspension can be maintained. A heat exchanger is operably associated with the blood circulation circuit and is effective to heat blood circulating in the blood circulation circuit.
It is an object of the invention to provide an apparatus which can effectively be used in whole body hyperthermia to control patient blood chemistries during the treatments, including effective control of calcium and phosphate levels.
Another object of the invention is to provide a sorbent suspension composition which is highly effective for use in sorbent-based hemodialysis to control patient blood calcium and phosphate levels in addition to other blood chemistries.
Another object of the invention is to provide an apparatus for use in supplying hemodialysis during whole body hyperthermia, which apparatus includes compliant membranes which promote mixing of sorbent suspensions and which are not overly tensioned by high rates of blood flow used during the treatments.
Additional embodiments, features and advantages of the present invention will be apparent from the following description.